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Infliximab is an anti-TNF-α monoclonal antibody approved in chronic inflammatory bowel diseases (IBD). This study aimed at providing an in-depth description of infliximab target-mediated pharmacokinetics in 133 IBD patients treated with 5 mg/kg infliximab at weeks 0, 2, 14, and 22. A two-compartment model with double target-mediated drug disposition (TMDD) in both central and peripheral compartments was developed, using a rich database of 26 ankylosing spondylitis patients as a reference for linear elimination kinetics. Population approach and quasi-steady-state (QSS) approximation were used. Concentration-time data were satisfactorily described using the double-TMDD model. Target-mediated parameters of central and peripheral compartments were respectively baseline TNF concentrations (R C  0  = 3.3 nM and R P  0  = 0.46 nM), steady-stated dissociation rates (K C  SS  = 15.4 nM and K P  SS  = 0.49 nM), and first-order elimination rates of complexes (k C  int  = 0.17 day −1  and k P  int  = 0.0079 day −1 ). This model showed slower turnover of targets and infliximab-TNF complex elimination rate in peripheral compartment than in central compartment. This study allowed a better understanding of the multi-scale target-mediated pharmacokinetics of infliximab. This model could be useful to improve model-based therapeutic drug monitoring of infliximab in IBD patients.

pharmaceutics

Infliximab Efficacy May Be Linked to Full TNF-α Blockade in Peripheral Compartment—A Double Central-Peripheral Target-Mediated Drug Disposition (TMDD) Model